1. Field of the Invention
The present invention relates to methods and substances for treating T-cell-mediated autoimmune diseases.
Autoimmunity is based on a specific, adaptive immune response against endogenous antigens. Normally, the immune system leaves endogenous substances undisturbed and combats only foreign bodies. Autoimmunity can be viewed as the result of a breakdown of the tolerance towards endogenous substances and/or of a defective control and regulation mechanism of the immune system. Admittedly the precise causes of the onset of autoimmune diseases are still unknown, however it is suspected that environmental and also hereditary factors are involved. T lymphocytes appear to be significantly involved in the triggering of the disease, since they can cause tissue damage both as cytotoxic T lymphocytes and also through the activation of macrophages.
Autoimmune diseases can be classified into tissue- or organ-specific and systemic, i.e., non-organ specific, autoimmune diseases. Thus for example the disease multiple sclerosis is an example of an organ-specific, T-cell-mediated autoimmune disease in man.
In practice, the therapeutic approach is limited by the chronic, slowly progressing nature of most auto-immune diseases. The use of immunosuppressants and corticosteroids has proved partially successful.
The course of chronic autoimmune diseases, allergies or infections can be predicted on the basis of the cytokine profile of CD4+ T helper (TH) cells. The TH lymphocytes are further subdivided inter alia on the basis of the cytokines produced by them: while TH1 cells synthesize interferon γ (IFN-γ) and interleukin-2 (IL-2), TH2 cells instead produce interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-9 (IL-9) and interleukin-13 (IL-13). A further TH cell population which produce cytokine IL-17, so-called TH17 cells, have a similar inflammatory phenotype to TH1 cells. IFN-γ producing TH1 cells control intracellular pathogens, but, like TH17 cells, can also trigger organ-specific autoimmune diseases such as for example autoimmune diabetes, multiple sclerosis or psoriasis, whereas IL-4 producing TH2 cells can ameliorate organ-specific autoimmune diseases.
The differentiation of native CD4+ cells in either TH1 or TH2 cells is regulated by cytokines, in particular by IL-12 or IL-4, and also by T cell receptor-ligand interactions, accessory molecules and the like. In addition, the functional phenotype of dendritic cells (DC), which are either TH1-inducing DC1 or TH2-inducing DC2, plays a part. For the formation of TH17 cells, the cytokine IL-23, which as well as its p19 chain has the same p40 subunit as IL-12, is necessary. Like IL-23, IL-12 is also produced by DC.
Glutathione (GSH) is a ubiquitously occurring tripeptide which is made up of the non-essential amino acids glutamate, cysteine and glycine. Because of its thiol group (SH group) and the γ-glutamyl linkage, glutathione has an abundance of biological functions which include detoxification reactions, structure formation of proteins, coenzyme functions, repair of DNA damage, and influencing of the cellular environment and hence involvement in developmental and ageing processes (ageing). Glutathione is possibly the most commonly occurring low molecular weight thiol and is found in almost all cells, in some cases at relatively high concentrations (about 5 mmol/l). The biosynthesis and degradation of glutathione proceed via the so-called γ-glutamyl cycle. As a sulfhydryl buffer in the cell, it is in equilibrium with glutathione disulfide GSSG, which is formed as an oxidation product either by catalytic action of a selenium-containing glutathione peroxidase, during which hydrogen peroxide arising in the metabolism is reduced, or in a transhydrogenation. An NADPH-dependent GSSG reductase catalyzes the reverse reaction to glutathione.
2. Related Prior Art
In recent studies (see Utsugi, et al., 2003, J. Immunol. 171, 628-635), it could be shown that compounds which are capable of forming glutathione-S conjugates inter alia suppress lipopolysaccharide-induced interleukin 12 production in macrophages.
In spite of said possibilities for treating autoimmune diseases, there is still great interest in finding alternative to the previously used therapeutic approaches, since said approaches often cause severe side-effects or can only be implemented very labor-intensively and/or at great expense.